Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Caspase-3 (32 kDa) is one of the primary protease executioners of apoptosis and is activated by intra-chain proteolytic cleavage, which generates a large subunit (17 kDa) and a small subunit (12 kDa). Typically, after apoptotic stimuli, the level of cleaved caspase-3 increases while that of caspase-3 decreases. It has been shown that caspase-3 mRNA levels increase in cortex following traumatic brain injury or focal ischemia. In the present study, we demonstrate that both caspase-3 mRNA and protein increase in apoptotic PC12 cells following exposure to manganese which strongly induces caspase-3 cleavage. Up-regulation of caspase-3 protein was evident in manganese-treated PC12 cells and was moderate in cisplatin-, rotenone- and A23187-treated cells but was not observed in serum deprivation-, anisomycin-, camptothecin-, cycloheximide- or staurosporine-treated cells in which all treatments induced extensive DNA fragmentation. Manganese-induced up-regulation of caspase-3 mRNA was partially attenuated by the pretreatment with the MEK inhibitor U0126, but not with the c-Jun N-terminal kinase (JNK) inhibitor SP600125. In contrast, the increase in caspase-3 protein was suppressed by both U0126 and SP600125. These results suggest that p44/42 MAPK contributes to the up-regulation of caspase-3 mRNA and the JNK pathway regulates caspase-3 protein levels posttranslationally in manganese-induced apoptosis in PC12 cells.
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PMID:p44/42 MAP kinase and c-Jun N-terminal kinase contribute to the up-regulation of caspase-3 in manganese-induced apoptosis in PC12 cells. 1678 41

The purpose of this study was to investigate whether latanoprost, a prostaglandin F2alpha analogue, has a direct anti-apoptotic effect both in retinal neuro-glial cells in culture and in diabetic retina. R28 cells, immortalized retinal neuroglial progenitor cells, were induced apoptosis by 24h serum deprivation. Serum withdrawal made up to 15% of R28 cells pyknotic and activated caspase-3 immunoreactive, and latanoprost acid suppressed apoptosis with dose dependency at an optimum concentration of 1.0 microM (P<0.001). UO126, a mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase (MEK) 1 and 2 inhibitor reversed this effect. Streptozotocin induced one- or three-month diabetic rats received balanced-salt-solution (BSS) in the left eye and latanoprost eye drops in the right for 5 days. Retinal wholemount was subjected to terminal dUTP nick end labeling (TUNEL) staining, whereas eyeballs were enucleated for cleaved caspase-3 immunofluorescence. Retinal homogenates were probed for phospho- or total p44/p42 MAPK and Akt. One- and three-month diabetic retina had 30.2+/-15.3 and 23.6+/-9.0 TUNEL positive cells per 0.5 cm(2), respectively, whereas control retina had few TUNEL positive cells. Latanoprost instillation significantly reduced these cells (10.0+/-3.1 and 11.3+/-3.1 cells per 0.5 cm(2) for 1M and 3M, respectively, P<0.01), whereas BSS did not. Latanoprost also significantly reduced cleaved caspase-3 immunoreactive cells in ganglion cell and inner nuclear layers (P<0.05). Latanoprost increased phosphorylated to total protein ratio of p44/p42 MAPK (P<0.05), but not of Akt. Taken together, the present findings suggest that latanoprost rescues retinal neurons and/or glial cells from apoptosis, which is probably mediated by p44/p42 MAPK through caspase-3 inhibition.
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PMID:Latanoprost rescues retinal neuro-glial cells from apoptosis by inhibiting caspase-3, which is mediated by p44/p42 mitogen-activated protein kinase. 1683 45

Dracorhodin perchlorate, an anthocyanin red pigment, induces human premyelocytic leukemia HL-60 cell death through apoptotic pathway. Caspase -1, -3, -8, -9, and -10 inhibitors partially reversed the cell death induced by dracorhodin perchlorate. Caspase-3 and -8 were activated followed to the degradation of caspase-3 substrates, inhibitor of caspase-activated DNase (ICAD) and poly-(ADP-ribose) polymerase (PARP). Dracorhodin perchlorate up-regulated the expression ratio of mitochondrial proteins, Bax/Bcl-XL. The cell death was accompanied with phosphorylation of ERK, JNK and p38 MAPK and partially reduced by MEK inhibitor (PD98059), JNK MAPK inhibitor (SP600125) and p38 MAPK inhibitor (SB 203580). Taken together, dracorhodin perchlorate-induced apoptosis in HL-60 cells via up-regulation of Bax, activation of caspases and ERK/p38/JNK MAPKs.
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PMID:Dracorhodin perchlorate induces apoptosis in HL-60 cells. 1686 44

Uncarinic acid E, an active component isolated from Gelsemium elegans BENTH, has been reported to exhibit antitumor effects, but little is known about its molecular mechanisms of action. In this study, the growth-inhibitory activity of uncarinic acid E for HepG2 cells is in time- and dose-dependent manner. HepG2 cells treated with uncarinic acid E exhibited several typical characteristics of apoptosis through photomicroscopical observation, DNA agarose gel electrophoresis. The inhibitory effect of uncarinic acid E on HepG2 cells was partially reversed by the inhibitors of pan-caspase, caspase-3 and caspase-6. The protein expression ratio of Bcl-xL/Bax and Bcl-2/Bax was down-regulated and uncarinic acid E-induced apoptosis involves the initial phase mediated by the balance among Bcl-xL, Bcl-2 and Bax proteins, resulting in cytochrome c release from the mitochondria. Uncarinic acid E significantly increased the expression of p53 proteins indicates that p53 plays a pivotal role in the initiation phase of uncarinic acid E-induced HepG2 cell apoptosis. The phoshatidylinositol 3-kinase (PI3-K) family inhibitor wortmanin and the MEK inhibitor (PD98059) rescued the viability loss induced by uncarinic acid E through the expression of p53. Taken together, uncarinic acid E induces apoptosis in HepG2 cells via accumulation of p53, alters the Bax/Bcl-2 ratio, and activates caspases, resulting in cytochrome c release from the mitochondria.
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PMID:The course of uncarinic acid E-induced apoptosis of HepG2 cells from damage to DNA and p53 activation to mitochondrial release of cytochrome c. 1688 Jun 19

Reactive oxygen species, including hydrogen peroxide (H(2)O(2)), are generated during ischemia-reperfusion and are critically involved in acute renal failure. The present studies examined the role of the extracellular signal-regulated kinase (ERK) pathway in H(2)O(2)-induced renal proximal tubular cells (RPTC) apoptosis. Exposure of RPTC to 1 mM H(2)O(2) resulted in apoptosis and activation of ERK1/2 and Akt. Pretreatment with the specific MEK inhibitors, U0126 and PD98059, or adenoviral infection with a construct that encodes a negative mutant of MEK1, protected cells against H(2)O(2)-induced apoptosis. In contrast, expression of constitutively active MEK1 enhanced H(2)O(2)-induced apoptosis. H(2)O(2) induced activation of caspase-3 and phosphorylation of histone H2B at serine 14, a posttranslational modification required for nuclear condensation, which also were blocked by ERK1/2 inhibition. Furthermore, blockade of ERK1/2 resulted in an increase in Akt phosphorylation and blockade of Akt potentiated apoptosis and diminished the protective effect conferred by ERK inhibition in H(2)O(2)-treated cells. Although Z-DEVD-FMK, a caspase-3 inhibitor, was able to inhibit histone H2B phosphorylation and apoptosis, it did not affect ERK1/2 phosphorylation. We suggest that ERK elicits apoptosis in epithelial cells by activating caspase-3 and inhibiting Akt pathways and elicits nuclear condensation through caspase-3 and histone H2B phosophorylation during oxidant injury.
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PMID:ERK promotes hydrogen peroxide-induced apoptosis through caspase-3 activation and inhibition of Akt in renal epithelial cells. 1688 55

Identifying the trophic factors for retina photoreceptors and the intracellular pathways activated to promote cell survival is crucial for treating retina neurodegenerative diseases. Docosahexaenoic acid (DHA), the major retinal polyunsaturated fatty acid, prevents photoreceptor apoptosis during early development in vitro, and upon oxidative stress. However, the signaling mechanisms activated by DHA are still unclear. We investigated whether the extracellular signal regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) or the phosphatidylinositol-3-kinase (PI3K) pathway participated in DHA protection. 1,4-Diamino-2,3-dicyano-1,4-bis(2-aminophynyltio) butadiene (U0126), a specific MEK inhibitor, completely blocked the DHA anti-apoptotic effect. DHA rapidly increased ERK phosphorylation in photoreceptors, whereas U0126 blocked this increase. U0126 hindered DHA prevention of mitochondrial depolarization, and blocked the DHA-induced increase in opsin expression. On the contrary, PI3K inhibitors did not diminish the DHA protective effect. DHA promoted the early expression of Bcl-2, decreased Bax expression and reduced caspase-3 activation in photoreceptors. These results suggest that DHA exclusively activates the ERK/MAPK pathway to promote photoreceptor survival during early development in vitro and upon oxidative stress. This leads to the regulation of Bcl-2 and Bax expression, thus preserving mitochondrial membrane potential and inhibiting caspase activation. Hence, DHA, a lipid trophic factor, promotes photoreceptor survival and differentiation by activating the same signaling pathways triggered by peptidic trophic factors.
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PMID:Docosahexaenoic acid prevents apoptosis of retina photoreceptors by activating the ERK/MAPK pathway. 1692 63

Arsenic trioxide (As(2)O(3)) induces both the differentiation and apoptosis of acute promyelocytic leukemia cells in a concentration dependent manner. We assessed the effects of As(2)O(3) in CADO-ES Ewing's sarcoma (ES), JK-GMS peripheral primitive neuroectodermal tumor (PNET), and SH-SY5Y neuroblastoma cells, as they share common histogenetic backgrounds. As(2)O(3) at low concentrations (0.1-1 microM) induced SH-SY5Y differentiation, and whereas PNET cells acquired a slightly differentiated phenotype, change was minimal in ES cells. Extracellular signal-regulated kinase 2 (ERK2) was activated at low As(2)O(3) concentrations, and PD98059, an inhibitor of MEK-1, blocked SH-SY5Y cell differentiation by As(2)O(3). High concentrations (2-10 microM) of As(2)O(3) induced the apoptosis in all three cell lines, and this was accompanied by the activation of c-jun N-terminal kinase. The generation of H(2)O(2) and activation of caspase 3 were identified as critical components of As(2)O(3)-induced apoptosis in all of the above cell lines. Fibroblast growth factor 2 enhanced As(2)O(3)-induced apoptosis in JK-GMS cells. The overall effects of As(2)O(3) strongly suggest that it has therapeutic potential for the treatment of ES/PNET.
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PMID:Arsenic trioxide concentration determines the fate of Ewing's sarcoma family tumors and neuroblastoma cells in vitro. 1693 May 95

We have previously shown that the HSV-2 anti-apoptotic protein ICP10PK is delivered by the replication incompetent virus mutant DeltaRR and prevents kainic acid (KA)-induced epileptiform seizures and neuronal cell loss in the mouse and rat models of temporal lobe epilepsy. The present studies used DeltaRR and the ICP10PK deleted virus mutant DeltaPK to examine the mechanism of neuroprotection. DeltaRR-infected neuronal cells expressed a chimeric protein in which ICP10PK is fused in frame to LacZ (p175) while retaining ICP10PK kinase activity. DeltaPK-infected neuronal cells expressed a mutant ICP10 protein that is deleted in the PK domain and is kinase negative (p95). p175 and p95 were expressed in CA3 (86+/-3%) and CA1 (69+/-7%) cells from DeltaRR or DeltaPK-infected organotypic hippocampal cultures (OHC) and 80-85% of the ICP10 positive cells co-stained with antibody to beta(III) Tubulin (neuronal marker). DeltaRR, but not DeltaPK, inhibited KA-induced cell death and caspase-3 activation in CA3 neurons, an inhibition seen whether DeltaRR was delivered 2 days before or 2 days after KA administration (95% neuroprotection). Neuroprotection was associated with ERK and Akt activation and was abrogated by simultaneous treatment with the MEK (U0126) and PI3-K (LY294002) inhibitors. DeltaRR-mediated neuroprotection was associated with increased expression of the anti-apoptotic protein Bag-1 and decreased expression of the pro-apoptotic protein Bad. The surviving neurons retained normal synaptic function potentially related to increased expression of the transcription factor CREB. The data indicate that DeltaRR is a promising platform for neuroprotection from excitotoxic injury.
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PMID:The growth compromised HSV-2 mutant DeltaRR prevents kainic acid-induced apoptosis and loss of function in organotypic hippocampal cultures. 1702 Jul 50

Advanced ovarian cancer (OC) is not curable by surgery alone and chemotherapy is essential for its treatment. Isothiocyanates have been shown to inhibit carcinogen-induced tumorigenesis in animal models, yet no efforts have been made to determine their therapeutic potential in OC. In the present study, we investigated the mechanism of the anti-proliferative and apoptotic activity of benzyl isothiocyanate (BITC) in OC. BITC inhibited the proliferation of OC cells and induced apoptosis in OC cells. Apoptosis was induced by a strong activation of caspase-3 and -9, and cleavage of PARP-1. However, caspase-8 was not activated by BITC. Cytotoxic effects of BITC were reversed by the inhibition caspase-3 and -9 specific inhibitors. BITC showed a concentration dependent decrease in the levels of Bcl-2 with a concomitant increase in Bax levels. In addition, BITC activated proapoptotic signaling by phosphorylation JNK1/2 and p38 while simultaneously inhibiting survival signaling mediated by ERK1/2 and Akt phosphorylation in a dose-dependent manner. While JNK inhibitor SP600125 and p38 inhibitor SB203580, abolished the cytotoxic effect of BITC, MEK inhibitor, PD98059 and PI3 kinase inhibitor, LY294002 failed to show such reversal indicating a critical role played by JNK1/2 and p38 signaling in apoptosis induced by BITC. In summary, our studies demonstrate that BITC inhibits proliferation of OC cells and induces apoptosis via caspase-9 and -3 pathways. BITC inhibits ERK1/2 and Akt survival signaling while simultaneously activating pro-apoptotic p38 and JNK1/2. Therefore, BITC can be potentially developed as a therapeutic agent to treat OC.
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PMID:Benzyl isothiocyanate (BITC) induces apoptosis in ovarian cancer cells in vitro. 1755 57

CEACAM1 (also known as CD66a) is a transmembrane glycoprotein that mediates homophilic intercellular interactions that influence cellular growth, immune cell activation, and tissue morphogenesis. Various studies have suggested a link between CEACAM1 and cellular apoptosis, including a recent demonstration that ERK1/2 signaling is triggered downstream of CEACAM1. In this study, we reveal that CEACAM1-long binding confers survival signals to human peripheral blood mononuclear cells. CEACAM-specific antibodies effectively protected peripheral blood mononuclear cells from apoptosis, with this effect being particularly dramatic for primary monocytes that undergo spontaneous apoptosis during in vitro culture. This protective effect was reiterated when using soluble CEACAM1, which binds to cell-surface CEACAM1 via homophilic interactions. Monocyte survival correlated with a CEACAM1-dependent up-regulation of the cellular inhibitor of apoptosis Bcl-2 and the abrogation of caspase-3 activation. CEACAM1 binding triggered a phosphatidylinositol 3-kinase-dependent activation of the protein kinase Akt without influencing the activity of extracellular signal-related kinase ERK, whereas the phosphatidylinositol 3-kinase-specific inhibitor LY294002 effectively blocked the protective effect of CEACAM1. Together, this work indicates that CEACAM1 confers a phosphatidylinositol 3-kinase- and Akt-dependent survival signal that inhibits mitochondrion-dependent apoptosis of monocytes. By controlling both ERK/MEK and PI3K/Akt pathways, CEACAM1 functions as a key regulator of contact-dependent control of cell survival, differentiation, and growth.
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PMID:CEACAM1 (CD66a) promotes human monocyte survival via a phosphatidylinositol 3-kinase- and AKT-dependent pathway. 1707 10


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